REverse LuNg Airway and Vascular RemOdeling in Asthma ReMission (ReNORM)

Обзор

In this program of research, the investigators aim to answer the question: In patients with asthma aged 18-80, how do the lung airways and vessels respond to biologic therapy and what role does age and asthma duration have in this response? While about 4.6 million Canadians live with asthma, \~5-10% of patients have severe asthma meaning that multiple inhaled and systemic oral corticosteroid treatments have failed to improve symptoms and exacerbations, leading to lost work and school days and substantially diminished ability to participate in normal life. For such people, the vast majority of whom are middle aged and remember asthma as part of their entire lifespan, biologic immunomodulator therapies, which block the function of asthma inflammatory pathways, provide a final step-up therapy option. There is emerging evidence that prescribed in the right patient at the right time, the right biologic can result in clinical remission of asthma. While spontaneous clinical remission of asthma is rare, it has been documented in children in whom lung growth and remodeling is still possible. It remains unknown whether clinical remission in adults is accompanied by the reversal of pathologic remodeling, at the level of the airways and pulmonary vessels. This is critical to elucidate as investigators and physicians move forward with currently proposed criteria for "complete asthma remission". The inconvenient truth about asthma and age is that in older adult lungs, exposed to years of infection, exacerbations, smooth muscle remodeling and pulmonary vascular shunt, the mechanisms by which complete pathologic remission may be achieved are complex and poorly understood. To address this knowledge gap, the investigators will evaluate 150 patients (Vancouver, Ottawa, Hamilton, London) (in three age tertiles 18-29; 30-59; 60-80) with severe asthma and 50 age- and sex matched healthy volunteers over 2-years using chest CT, MRI and pulmonary function tests. The investigators will use the pulmonary imaging measurements to generate an imaging-index of normal airway structure and function which will be compared with and significantly correlate with MR-guided bronchoscopic sample measurements made before and after 1-/2-years of treatment. The investigators will reveal the pathobiologic relationship between age, asthma duration, clinical remission and imaging normalization with direct comparison to histology-based airway measurements.

Вмешательства

• Биопрепарат Biologic Therapy
  Participants with severe asthma (GINA 5) who are eligible to begin biologic therapy. Participants will undergo serial assessment with pulmonary imaging (CT, MRI), lung function testing, sputum collection, and symptom questionnaires. A subset of participants (\~15%) will be randomized to undergo MRI-guided bronchoscopy with airway sampling at baseline and 2 years.

Первичные конечные точки

• Determine extent of imaging-based remission in patients with severe asthma following 1 and 2 years of biologic therapy [Срок оценки: from baseline to year 1 and year 2]
• Measure the extent and timing of clinical remission in patients with severe asthma as measured by changes in spirometry measurements of FEV1 and FVC [Срок оценки: from baseline to 1 year and 2 years]
• To determine the extent and timing of clinical remission in patients with severe asthma using symptoms scores of ACQ-5 and ACT [Срок оценки: From baseline to 1 year and 2 years]
• Determine the extent and timing of imaging-based remission in patients with severe asthma using CT airway and vessel morphology [Срок оценки: From baseline to 1 year and 2 years]
• To determine the extent and timing of clinical remission using the clinical outcome of frequency of asthma exacerbations in patients with severe asthma [Срок оценки: from baseline to 1 year and 2 years]
• To determine the extent and timing of clinical remission of patients with severe asthma using the clinical outcome of OCS use [Срок оценки: From baseline to 1 year and 2 years]
• Determine the extent and timing of clinical remission in patients with severe asthma as measured by sputum and blood eosinophil counts [Срок оценки: From baseline to 1 year and 2 years]

Вторичные конечные точки (12)

• Timing and proportion of patients achieving clinical remission after biologic treatment as measured by FEV1 and FVC. [Срок оценки: From baseline to 1 year and 2 years]
• To determine the timing and proportion of patients achieving clinical remission as measured by ACQ-5 and ACT questionnaires. [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving clinical remission after biologic treatment using FeNO. [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving clinical remission using DLco. [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving clinical remission after biologic treatment using SGRQ score. [Срок оценки: From baseline to 1 year and 2 years.]
• Determine the timing and proportion of patients with severe asthma achieving clinical remission on biologic treatment using AQLQ scores. [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using 129-Xe MRI VDP [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using CT metrics [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using DLco. [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using RV/TLC [Срок оценки: From baseline to 1 year and 2 years]
• Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using FRC. [Срок оценки: From baseline to 1 year and 2 years]
• Determine the relationships between clinical and imaging remission and generate predictive models for their achievement using changes in VDP [Срок оценки: from baseline to 12-weeks and 2-years]

Критерии участия

Критерии включения

Participants eligible for inclusion in this study must meet all the following criteria:

• Participant understands study procedures and is willing to participate in the study as indicated by the patient's signature.
• Provision of written, informed consent prior to any study specific procedures.
• Males and females aged 18 to 80 years.
• Either diagnosed with severe asthma (GINA Step 5) and newly eligible for biologic therapy (based on ACQ-5, current treatment, exacerbation history, and blood eosinophils in accordance with approved criteria for omalizumab, mepolizumab, benralizumab, dupilumab, or tezepelumab), or a healthy volunteer with no history of chronic lung disease, matched by age and sex. Healthy participants must have a lifetime combustible tobacco and/or cannabis (including vaping) consumption of ≤5 pack-years.
• Women of childbearing potential (after menarche) must ensure that they are using an effective form of birth control for at least 2 months prior to each imaging visit. Examples of effective birth control include:

• True sexual abstinence
• A vasectomized sexual partner
• Implanon®
• Female sterilization by tubal occlusion
• Effective intrauterine device (IUD)/levonogestrel intrauterine system (IUS)
• Depo-Provera™ injections
• Oral contraceptive
• Evra Patch™
• Nuvaring™
• Women of childbearing potential (after menarche) must agree to use a highly effective form of birth control, as defined above, from enrollment, throughout the study duration, and 8 weeks after last dose of study drug, with negative urine pregnancy test result at Visit 1-5.
• Male participants who are sexually active must agree to use a double barrier method of contraception (male condom with diaphragm or male condom with cervical cap) from the first dose of the study drug until 8 weeks after last dose

Критерии исключения

Participants fulfilling any of the following criteria are not eligible for inclusion in this study:

• Patient has an implanted mechanically, electrically, or magnetically activated device or any metal in their body which cannot be removed, including but not limited to pacemakers, neurostimulators, biostimulators, implanted insulin pumps, aneurysm clips, bioprosthesis, artificial limb, metallic fragment or foreign body, shunt, surgical staples (including clips or metallic sutures and/or ear implants) (at the discretion of the MRI Technologist).
• In the investigator's opinion, subject suffers from any physical, psychological or other condition(s) that might prevent performance of the MRI or CT, such as severe claustrophobia.
• Participants who are pregnant, breastfeeding or have a positive pregnancy test at initial screening visit.
• Participant is unable to perform spirometry or plethysmography maneuvers.
• Participant is unable to perform MRI and CT breath-hold maneuvers.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Канада · 1 центр

• Robarts Research Institute; The University of Western Ontario — London

Идентификаторы

NCT: NCT07174713 · ROB0061

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗